DK167765B1 - ANALOGY PROCEDURE FOR PREPARATION OF 2-BETA-D-RIBOFURANOSYLSELENAZOLE-4-CARBOXAMIDE COMPOUNDS - Google Patents

Description

in DK 167765 B1

The present invention relates to an analogous process for the preparation of novel 2-O-D-ribofuranosyl selenazole-4-carboxamide compounds having pharmacological action, in particular antitumor and antiviral activity.

5

Combating malignant tumors in humans and animals remains an unreachable goal. Within the last several decades, the understanding of malignancy has made significant progress, but overcoming the malignancy of the malignancy has not been achieved.

Conventional treatment of both humans and other valuable animal species plagued by malignant tumors currently includes surgical cutting of the tumor, local radiation therapy of the affected animal, and chemotherapy in the administration of a chemotherapeutic agent to the animal. The death of a significant number of patients affected by malignant tumors is not due to the primary tumor, but instead metastases from the primary tumor to 20 secondary sites of the host. If a primary tumor is detected early, it can usually be removed by surgery, radiation or chemotherapy or combinations thereof. However, the metastasis colonies from these primary tumors are significantly more difficult to detect and remove, and the 25 unsuccessful treatment of them remains a serious medical problem.

Tumors are usually classified as benign or malignant. The malignant tumor is characterized by its ability to both penetrate into surrounding tissues and to infect distant sites via metastasis. Some organs are more susceptible or susceptible to metastasis than others. To this group, the lungs, brain, liver, ovaries and adrenal glands will belong. It has also been expected that in some cases both surgery and radiation of a primary tumor actually promote metastasis.

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2

Due to the inability of current cancer treatment to successfully fight the malignant tumor and its metastasis, there is a need for additional chemotherapeutic agents.

5 Similarly, agents are currently available to combat and treat antiviral infections, but few of these agents are clinically useful and are only active in a narrow range. Therefore, there is also a need in this field 10 for additional chemotherapeutic agents, especially for agents having both antiviral and anti-tumor effects.

The present invention relates to an analogous process for the preparation of novel 2- / 3-D-ribofuranosylselenazole-4-carboxamide compounds of the general formula: 20 N- See R ° (jH2 to r20 OR1 wherein R 1 and R 2 are each hydrogen, lower alkanoyl or benzoyl and R 3 is hydrogen, lower alkanoyl, benzoyl or O 'H0-P-;

30 OH

and when R 3 is phosphono, physiologically acceptable salts thereof.

Preferred by the process of the invention are compounds as follows: DK 167765 B1 3 2- / 3-Dr ibof uranosy Iselenazole-4-carboxamide 2- (2,3,5-tri-O-acetyl-0-D (ribofuranosyl) selenazole-4-carboxamide, 2-O-D-ribofuranosylselenazole-4-carboxamide-51-phosphate, and 2-O-D-ribofur anozyl Isel enazole-4-carboxam in d-5 ' -phosphate, sodium salted.

The compound 2-0-D-ribofuranosylselenazole-4-carboxamide, hereinafter sometimes referred to as compound 1, has been shown to exhibit significant anti-tumor effect in vivo and significant antiviral effect in vitro. Agents containing this compound and / or ester derivatives of formula I can be used to treat malignant tumors in warm-blooded animals. The anti-tumor properties of 2-O-D-ribofuranosylselenazole-4-carboxamide and its derived esters are utilized in administering to a warm-blooded animal an effective amount of a pharmaceutical agent containing as an active ingredient at 0.1% by weight, based on the total weight of the agent, of at least one compound of formula I.

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Furthermore, agents containing the compound 1 and / or ester derivatives of formula I can be used to treat viral infections in warm-blooded animals. The antiviral properties of 2-O-D-ribofuranosylselenazole-4-carboxamide and esters thereof are utilized by administration to a warm-blooded animal of an effective amount of a pharmaceutical agent containing as an active ingredient at least approx. 1.0% by weight, based on the total weight of the agent, of at least one compound of formula I.

Particular meanings of R *, R 2 and R 3 in the compounds of the invention as preferred alkanoyl groups are acetyl, propinyl, butyryl and isobutyryl. As preferred salts where R 3 is phosphono may be mentioned alkali metal salts and ammonium salts or substituted ammonium salts such as the sodium, potassium or ammonium salt.

When R 1 and R 2 are both H, R 3 is preferably H, C 2 -C 8 alkanoyl, DK 16776b ΒΊ 5 4 Ο

II

or ΗΟ-Ρ-, and when R 1 and R 2 are both C 1 -C 8 alkanoyl, R 3 is OH

Ci-Cg alkanoyl.

Pharmaceutical agents containing the compounds of the present invention can be prepared in any suitable manner, preferably together with an inert carrier. The pharmaceutical carrier is preferably selected to allow the administration of a suitable concentration of the agent as a solution or suspension by injection into an infected warm blooded animal. Depending on the host that houses the malignant tumor, the type of tumor and the site of the tumor, or, depending on the viral infection and infection type and site of infection, the administration by injection may be intravenous, intramuscular, intracerebral, subcutaneous or intraperitoneal. .

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Alternatively, the agent may be formulated with a suitable pharmaceutical carrier which enables administration by another route, such as oral, ophthalmic, topical or as a suppository.

The alkanoyl groups may be selected from straight-chain, branched, substituted, unsaturated, saturated or aromatic acids such as, but not necessarily limited to, acetic acid, trifluoroacetic acid, propionic acid, n-butyric acid, isobutyric acid, valeric acid, capric acid, pelargonic acid, pelargonic acid, , benzoic acid, phthalic acid, salicylic acid, cinnamic acid and naphthalene carboxylic acid. In the case of phosphate compounds prepared by the process of the invention, the phosphoryl ester may be present as a free acid or in salt form. Acceptable salts of the phosphate moiety may be selected from, but not necessarily limited to, a group consisting of alkali and alkaline earth metals, e.g. sodium, potassium, calcium, magnesium and lithium, ammonium and substituted ammonium comprising trialkylammonium, dialkylammonium and allylammonium, e.g.

DK 167765 B1 5 triethylammonium, trimethylammonium, diethylammonium, octylammonium and cetyltrimethylammonium and cetylpyridinium.

The process of the invention is characterized by: a) subjecting an alkyl 2- (2,3,5-tri-O-acyl- / 3-D-ribofuranosyl) selenazole-4-carboxylate ammonolysis; b) phosphorylates 2-O-D-ribofuranosylselenazole-4-carboxamide, c) acylates 2-O-D-ribofuranosyl-1-selenazole-4-carboxamide, and isolates the product, optionally in the form of a salt.

The ammonolysis reaction to prepare 2- / 3-D-ribofuranosyl-selenazole-4-carboxamide (Compound 1) is carried out in a suitable solvent such as methanol. The reaction conditions can be varied, such as e.g. at ambient temperature and pressure, preferably at room temperature, until the reaction is complete, e.g. for approx. 24 hours. The product is isolated from the reaction mixture in any suitable manner, such as by column chromatography. The alkyl and acyl groups of the starting material can be varied within wide limits since they are removed during the reaction and the choice thereof is thus not critical. Preferred alkyl groups are C 1 -C 6 alkyl groups. Preferred acyl groups are the acetyl group, the n-butyryl group and the benzoyl group.

The phosphorylation reaction to prepare the 2-pD-ribofuranosyl selenazole-4-carboxamide-5'-phosphate compounds is carried out by said compound 1 and a phosphorylating agent such as phosphoryl chloride, advantageously in the cold, in a suitable medium such as triethyl phosphate or pyridine and acetonitrile. The product is isolated from the reaction mixture in any suitable manner, such as by ion exchange chromatography. Acylation is carried out by reacting compound 1 with the acylating agent, such as an acid anhydride or acid chloride, preferably in excess at ambient temperature until the reaction is complete.

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The invention and the best way to practice it are described in the following examples.

Example 1 S.

2-β-D-ribofuranosylselenazole-4-carboxamide, Compound 1 2,5-anhydro-3,4,6-tri-O-benzoyl-D-alzeneselenocarboxamide.

a) A mixture of 2,3,5-tri-O-benzoyl-8-P-ribofuranosyl = 10 cyanide (10, and, 21.2 mmol), 4-axmethylaminopyridine (200 mg) and liquid hydrogen selenide (condensed under a atmosphere, 20 ml) was stirred in a closed bomb at room temperature for 20 hours. Hydrogen selenide was allowed to evaporate. The dark colored residue was dissolved in chloroform 15 (200 ml) and washed successively with water (3 x 50 ml), saturated NaHCO 3 (3 x 50 ml) followed by water (2 x 50 ml). The chloroform portion was dried (MgSO4) and evaporated in vacuo to give the subtitle product as a foam in almost quantitative yield. The latter product with analyzer unit was obtained by column chromatography (silica gel, 5% ethyl acetate in chloroform).

The product developed a violet color when the silica gel chromatogram of the product was sprayed with a dilute etha = 25 nol solution of 2,3-dichloro naphthoquinone and exposed to ammonia. Analysis calculated for C2-7C23-780: C 58.91; H, 4.21; See 13.98. Found: C, 58.81; H, 4.29; N, 2.51; See 13.74.

Reaction of 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allone seleno-30-carboxamide with ethyl bromo-pyruvate and synthesis of ethyl 2- (2,3,5-tri-o-benzoyl-D (ribofuranosyl) selenazole-4-carboxy = later.

b) A solution of 2,5-anhydro-3,4,6-tri-O-benzoyl-D-35 allone selenocarboxamide (5.5 g, 10 mmol) in acetonitrile (60 ml) was cooled in ice. Ethyl bromo-pyruvate (3.0 g) in acetone = tril (20 ml) was added dropwise (10 minutes). The ice bath DK 167765 B7 was removed and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and the residue was triturated with a saturated sodium bicarbonate solution (100 ml) and extracted with ethyl = 5 ether (2 x 100 ml). ). The combined ether portion was washed with water and dried (MgSO 4). The ether was evaporated in vacuo and the residue (syrup) passed through a silica gel column (300 g), contained in chloroform. Elution with 5% ethyl = acetate in chloroform resulted in products of the subtitle: namely the fast moving ethyl 2 (2,3,5-tri-O-benzoyl-2-BD-ribofuranosyl) selenazole-4-carboxylate ( 2.5 g) and the slow-moving ethyl 2- (2,3,5-tri-O-benzoyl-2-ct-D-ribofuranosyl) selenazole-4-carboxylate (1.0 g) isolated after evaporation under reduced pressure in the form of viscous syrups, the β-isomer, ethyl 2- (2,3,5-tri-O-benzoyl-2-pD-ribofuranosyl) selenazole-4-carboxylate, is characterized by an optical rotation , 1.07% in methanol, [α] ρ5 = 34.7 °. Analysis calculated for C 32 H 27 NO 2 Se (648.51): C 59.26; H, 4.20; N, 2.16. Found: C, 59.44; H, 4.21; N, 1.89.

Compound 1.

c) Ethyl 2- (2,3,5-tri-O-benzoyl-BD-ribofuranosyl) se = lenazole-4-carboxylate (3.2 g, 5 mmol) was dissolved in methanol (100 ml) , chilled and saturated with ammonia (0 ° C). The solution was stirred in a pressure flask at room temperature for 48 hours. The solvent was evaporated in vacuo and the residue was extracted with chloroform (3 x 25 ml).

The amount of chloroform was discarded. The residue was adsorbed on silica gel (10 g) by methanol and applied to a silica gel column (2.8 x 45 cm) contained in ethyl acetate. The column was eluted with solvent E (ethyl acetate, n-propanol, H 2 O; 4: 1: 2; v / v: upper layer forming solvent E) and the homogeneous fractions (R f = 0.42, silica gel-tlc solvent E) containing the main product was collected. The solvent was evaporated

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8 in vacuo, and the title compound was crystallized as residue from 2-propanol: yield 900 mg of the title compound, compound 1, (60%), mp 135-136 ° C. The residue resulted in another yield (200 mg), mp 5 131-133 ° C. Analysis calculated for cg H 2 N 2 O 5 Se: C 35.19; H, 3.94; N, 9.12; See 25.71- Found: C, 35.43; H, 3.97; N, 9.03;

See 25.55. [.alpha.] @ 5, 1.07% in methanol, -22.2 °. LD10, acute toxicity, 96.5 mg / kg by intraperitoneal injection in mice.

Example 2 2- / S-D-ribofuranosylselenazole -4-carboxamide-5 'phosphate, compound 2.

Water (151 mg, 8.4 mmol) was carefully added to a solution (maintained at 0 ° C by stirring) of phosphoryl = chloride (2.0 g, 13.2 mmol), pyridine (1.21 g , 14.4 mmol) and acetonitrile (2.3 g, 56.7 mmol). 2-8-D-ribofuranosyl = selenazole-4-carboxamide (921 · mg, 3.0 mmol) was added to the solution and the reaction mixture was stirred for 4 hours at 0 ° C. A clear solution was obtained and poured into ice-water (50 ml), after which the pH was adjusted to 2.0 with concentrated sodium hydroxide. The solution was applied to an active carbon column (30 g) and the column was thoroughly washed with water until the eluate was salt free. The column was eluted with a solution of ethanol / water / concentrated ammonium hydroxide (10: 10: 1) and the fractions (each of 25 ml) were collected. The fractions containing the nucleotide title compound, compound 2, in pure form (tic, silica gel, acetonitrile-0.1 N ammonium = chloride (7: 3)) were collected and evaporated to dryness under vacuum. The anhydrous residue, compound 2, was dissolved in water and passed through a column of "Dowex" 50W-X8 (20 - 50 mesh, H + form, 15 ml) - The column was washed with water and the fraction containing the nucleotide collected. The solution was evaporated to a small volume (5 ml) and passed through a column of "Dowex" 50W-X8 (20 - 50 mesh, Na + form, 15 ml). The column was washed with water. The fraction containing the nucleotide in the form of the sodium salt was lyophilized. The residue was triturated with ethanol, collected by filtration, and dried (P205) 5 to give 580 mg (42%) of 2- | 3-D-ribofuranosyl selenazole-4-carboxamide-5'-phosphate as monosodium trihydrate in the crystalline form. Analysis calculated for C 9 H 21 N 2 ° 8 = PSeNa, 3H 2 O: C, 23.33; H, 3.90; N, 6.05; P, 6.69; See 17.04.

Found: C, 23.01; H, 3.76; N, 5.86; P, 7.02; See 16.32.

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Example 3 2- (2,3,5-Tri-O-acetyl-O-D-ribofuranosyl) selenazole-4-carboxamide Compound 3.

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A mixture of 2-8-D-ribofuranosylselenazole-4-carboxamide (1.0 g, 3.25 mmol), Ν, Ν-dimethylaminopyridine (catalyst, 80 mg) and acetic anhydride (15 ml) was stirred at room temperature for 3 hours. . The solvent was evaporated in vacuo and evaporated simultaneously with water (2 x 10 ml) to give Compound 3 as a white crystalline product which was triturated with water and collected by filtration. The product was recrystallized from water containing a few drops of ethanol to give white 25 needles in a yield of 1.2 g (85%), mp 117-111 ° C. Analysis calculated for c15 H18 N2 O2 Se: C, 41.58; H, 4.19; N, 6.47; See 18.22. Found C 41.80; H, 4.30; N, 6.58;

See 17.97. Corresponding 2 ', 3', 5'-0-acyl compounds of the invention are prepared from Compound 1 by this procedure by reacting the latter with the appropriate acid anhydride until the reaction is complete and isolating the product in pure form. 1 10

Illustrative examples of the anti-tumor use of compounds 1 and 2 are given below Examples 4 to 6. These examples demonstrate the effectiveness of the compounds using standard experiments above 5 for a malignant tumor, Lewis's lung carcinoma. The experiments used in these illustrative examples were carried out by the Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute. The experiments were monitored by this undertaking using its standard regulations and procedures. All tests were performed in accordance with these regulations and all tests were evaluated according to the criteria defined under these regulations. The following representative examples illustrate in 15 affirmative action the illustrative compounds of the invention against sorting tumor systems according to the National Cancer Institute.

For the purposes of the following examples, the abbreviation stands for IP

20 for intraperitoneal, and IV for intravenous. Mean and median survival times are calculated in instruction 14 (revision 6/78) of the Screening Data Summary, Develop = Mental Therapeutics Program, Division of Cancer Treatment,

National Cancer Institute. The contents of this sorting data summary, including corresponding revisions, are incorporated herein by reference. In the examples illustrated below, the carrier used for the drug was injected (minus 30 any drug therein) into the control animals in the same amount of use of the matrix as for the drug treated animals to eliminate any matrix effect in the experiments.

2-3-D-ribofuranosylselenazole-4-carboxamide, Compound 1, is listed as active against Lewis lung cancer according to Example 4 and successfully met the DN (decision network) 2 criteria of the National Cancer Institute Testing. For example 4 ', BgD2F1 ~ 11 was used

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male mice that were infected with Lewis lung carcinoma. The median survival time of the test animals was compared to the median survival time of similar control animals. Based on this criterion, Compound 1 was considered to be an effective antifungal agent.

In Example 4, 40 control animals and 10 test animals were used, each animal at dose levels listed below in Table 1. Both in the control group and in the drug-treated group, tumors were induced by zero-day IV injection followed by starting drug treatment on day 1. In Example 4, water was used as the matrix for the drug.

In both the control group and the drug-treated group of Example 4, the animals were zero seeded on the day with a g homogenate of 10 seed cells of Lewis lung carcinoma. In Example 12, drug treatment was started on day 1 and compound 1 was administered once daily for 9 days. The 5th day was used as the day of death, which was attributable to the drug's toxicity. In this example, there was no mortality attributable to the toxicity of the drug. Treatment efficacy was determined by comparing the median survival time of the control animals and it is expressed as percentage increase in treated animals / control animals (T / C).

The trial period was 60 days, and at the end of the 60-day period, all surviving animals in the experimental groups were rated as either cured, non-susceptible or tumor survivors.

Example 4._ 35 In this example, the drug-tested animals were injected IP with the dose amount listed in Table 1 below.

Ten animals were treated at each dose level. No control animals survived after day 23 with a median date of death

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on day 19.0. At dose levels of 75 and 13 mg / kg, all treated animals survived, implying a T / C of 315% and 7 out of 10 and 5 out of 10 cures, respectively. Furthermore, at the relatively low dose of 3 mg / kg, the 5 DN2 criterion according to NCI was met by obtaining a T / C

of 152%. 1 cure was achieved at this dose.

Compound 1 is listed as an active anti-tumor compound in the multidose studies listed.

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Table 1.

Anti-tumor effect - compound 1.

15 Drug-Treated Control Health- Percent dose group, group, claimant treated mg / kg survival-survival animal / control-time - time animals.

75 60.0 19.0 7/10 315% 20 50 18.0 1/10 94% 33 18.0 3/10 94% 20 16.0 2/10 13 60.0 5/10 315% 9 10, 4 3/10 25 6 12.0 1/10 3 28.9 1/10 152%

As shown in Table 1, Compound 1 exhibits excellent efficacy against Lewis lung carcinoma. Lewis's lung carcinoma 30 is a prime example of a metastatic tumor system. The test animals and control animals were inoculated in Example 12 with a homogenate of the tumor. Dramatic expression of this tumor is then seen in the lungs. The ability of metastasis formation is a feature that specifically characterizes a malignant tumor compared to a benign tumor.

DK 167765 B1 13

Example · 5.

In this example, compound 1 was tested in BrD "F" females infected with Lewis lung carcinoma. The median survival time of the test animals was compared to the median survival time of the corresponding control animal · On the basis of this criterion, compound 1 proved to be an effective anti-swelling agent as shown in Table 2. At dose levels of 50, 25 and 12.50 mg / kg, all survived the test animals, leading to a T / C of 355%.

6 out of 10, 7 out of 10 and 8 out of 10 cures were respectively obtained.

Table 2.

Anti-tumor effect - compound-1.

Drug-Treated Control Health- Percent 20 dose group, group, claimant treated rogAg survivor survival animal / control time animal.

200 10.7 16.9 0/10 25 100 20/3 3/10 120 50 60.0 6/10 355 25 60.0 7/10 355 12 60.0 8/10 355

Compound 1 was further tested in a Lewis lung 30, xn vivo mouse model using B ^ D ^ F, female mice that were infected with Lewis lung carcinoma. The results are listed in Table 3. As shown, compound 1 in low dose amounts (24, 12 and 6 mg / kg) leads to a T / C of 297%.

9 out of 10, 9 out of 10 and 5 out of 10 complete 35 degrees were respectively obtained. Compound 1 produced a DN2 efficiency (percent T / C greater than 150) of 153 at the low dose of 3 mg / kg. The results confirm that Compound 1 is an effective antifungal agent for Lewis lung carcinoma in mice.

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Anti-tumor effect - compound 1.

5 DK 167765 B1

Table 3.

Drug-Treated 'Control Health- Percentage dose group, group, claimant treated iaq / kq survival-survival animal Control-time animal.

10 _ * _ 24.00 60.0 20.2 9/10 297 12.00 60.0 9/10 297 6.00 60.0 5/10 297 3.00 31.0 0/10 153 15 1.50 22.3 0/10 110 0.75 21.7 0/10 107

Example 6 20

Compound 2, 2- (5-phosphono-β-D-ribofuranosyl) selenazole-4-carboxamide was tested for efficacy against Lewis lung carcinoma in a manner similar to that described in Example 4. In this example, male B6D2F1 mice were infected with Lewis lung carcinoma. The mean survival time of the 25 test animals was compared to the mean survival time of similar control animals. On the basis of this criterion, compound 2 was considered an effective anti-tumor agent. In this example, cures ranging from 1 in 10 to 4 in 10 were obtained at a dose ranging from 30 9 mg / kg to 75 mg / kg as shown in Table 4 below.

At 13 mg / kg, the treated surviving mice have a T / C of 315% and 4 out of 20 cures were achieved.

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Anti-tumor effect - compound 2.

DK 167765 Pg 15

Table 4.

5 Drug-Treated Control Health- Percent dose group, group, claimant treated mgAg survivor survivor animalsControl time animals.

75 15.5 19.0 1/10 10 50 12.5 3/10 33 12.5 3/10 20 12.0 2/10 13 60.0 4/10 315 9 12.5 1/10 15 6 22 , 0 0/10 115 3 20.8 0/10 109

In further experiments, growth inhibitory effects of Compound 1 and Compound 2 were measured against 3 mouse 20 genera in suspension cell culture. Cell cultures were initiated at a density of 50,000 cells / mg in the medium. RPftE 1630 supplemented with 10% fetal calf serum. The composition of this culture medium and details of the culture procedure followed the published method (G. E.

25 Morre, A. A. Sandberg, and K. Ulrich, Suspension Cell

Culture and in vivo and in vitro chromosome constitution of mouse leukemia L1210, Journal of the National Cancer Institute _36, 405-415, 1966). Cultures were maintained at 37 ° C in stationary suspension culture under an atmosphere 30 of 95% air + 5% CO 2 · Experimental compounds were added to treated cultures at the time of initiation and were continuously present. After 72 hours, 40-fold dilutions of drug-treated and untreated control cultures were prepared in 0.9% NACl solution, and cells were counted with an electronic particle counter. The results of the experiments are shown in Table 5 below.

The growth inhibitory effects are expressed as IDgQ values, namely inhibitory doses or test compound concentrations required to decrease cell count in treated cultures to 50% of cell count in untreated control cultures.

Table 5.

ID ^ q values (molar) against different tumor cell lineages.

L-1210 P388 B ^ gMelanoma

Compound 1 4.0 x 10 ~ 7 2.7 x 10 ~ 7 3.5 x ΙΟ-6

Compound 2 5.8 x 10 "8 6.6 x 10 ~ 8 7.5 x 10" 6

These results show that Compound 1 and Compound 5 2 both inhibit cell culture growth of representative low-dose tumor genera. In this regard, the 51-phosphate (compound 2) is found to be superior to compound 1 '

Example 7 10 In one embodiment, Compound 1 exhibited activity against both small and large viruses of both DNA KNA types by the virus assessment method (VR) of Sidwell et al., Appl. Microbiol. 22, 797 (1971). A virus rating greater than 1.0 indicates a definite antiviral effect. A virus rating of 0.5 - 0.9 indicates moderate antiviral activity and a virus rating of less than 0.5 indicates little or no apparent antiviral effect. The results set forth below were obtained by testing on "Microtest" II (Falcon Plastics) plastic sheets 20 with a monolayer of Vero or HeLa cells.

Antiviral effect of compound 1.

DK 167765 B1 17

Virus ED (q / µg / ml) dosing

Virus Vero HeLa Vero HeLa ENA viruses.

Para 3 2.6 2.2 1 1 Measles 2.0 1.8 1 2 Sheep disease 1.7 1.0 5 1

Eeo 3 1.8 2.7 1 8 VSV 0.4 2.1 1000 9

Cox Bl 1.7 1.8 15 10

Cox B4 0.0 2.3 1000 6.

DM viruses.

W 2.1 2.4 3 2

Ad-2 1.9 9 HSV-1 1.2 1.4 30 2 HSV-2 1.5 1.5 10 4

The results show that compound 1 has a good broad-spectrum antiviral effect against both DNA and RNA viruses. Of the DNA viruses, the representatives of the families 5 Poxviridae (Vaccinia) and Herpesviridae (HSV-1, HSV-2) were most inhibited. The greatest effect was observed against the representatives of the KNA families Paramyxoviridae (para-3, mumps, measles) and Reoviridae (Reo-3). Superior antiviral activity was measured in HeLa cells for the 10 families of Adenoviridae (Adeno-2), Picornaviridae (Cox B1, Cox B4) and Rhabdoviridae (VSV).

The studies further show that antiviral action of compound 1 is both viral (against Vaccinia)

Claims (4)

Compound 1 is non-toxic to Vero, HeLa, and MRC-5 cells at levels of 1000 µg / ml (the highest concentration tested). These results further demonstrate that compound 1 inhibits viral cytopathic effects in cell culture for 10 representative viruses at extremely low dose. Compound 1 exhibits low cytotoxicity and is soluble in aqueous media. Claims. 1. Analogy Process for Preparation of 2 - / 3 - D - Ribof urano - Silselenazole-4-Carboxamide Compounds of the General Formula: O t / -CN-H2N 1I x • S / 3® R R is each H, lower alkanoyl or benzoyl, and R is H, lower alkanoyl, benzoyl or O II H0-P-; OH DK 167765 B1 19 and when R3 is phosphono, physiologically acceptable salts thereof, characterized in that: aj is subjected to an alkyl 2- (2,3,5-tri-O-acyl- / JD-ribofuranoyl) selenazole -4-carboxylate ammonolysis; . A process according to claim 1 for the preparation of 2-O-D-ribo-furanosylselenazole-4-carboxamide characterized in that an alkyl 2- (2,3,5-tri-O-acyl-jff-D-ribofuranosyl) ) selenazole-4-carboxylate as starting material is subjected to ammonolysis. A process according to claim 1 for the preparation of 2-D-ribofuranolylselenazole-4-carboxamide-5'-phosphate, characterized in that 2- / 3-D-ribofuranosylselenazole-4-carboxamide is phosphorylated. Process according to claim 1 for the preparation of the sodium salt of 2 form of the sodium salt. A process according to claim 1 for the preparation of 2- (2,3,5-tri-O-acetyl 1-8-Dr ibof uranosyl) selenazole-4-carboxamide, characterized in that 2- / 3-D-ribofuranosylselenazole 4-carboxamide is acetylated.